The mammalian immune system is a complex network that serves to protect a subject from external and internal endangering factors. However, in some circumstances, this complex protection mechanism sustains or itself becomes a cause of disorders, mostly with chronic implications, within the subject. Many such immune disorders exist, two important ones being the allergic diseases and the autoimmune disorders. Allergic diseases, conventionally described as type-1 mediated diseases or IgE-mediated diseases, have seen their prevalence almost doubled over the last 20 years. Clinical manifestations of allergic diseases include bronchial asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and anaphylactic reactions to insect bites or drugs. The economical burden related to the care of allergic patients is steadily increasing over the years. As an example, the cost linked to prescription of allergy treatment in the US is anticipated to reach around 10 billion US dollars in 2006. There is currently no curative therapy for such diseases, which are kept under control by allergen eviction whenever possible, and/or by symptomatic therapy using bronchodilators, anti-histamines, corticosteroids and immunomodulators such as cyclosporine. Allergen desensitisation, which consists in regular administration of allergens to which the patient is sensitised, has shown efficacy in allergic rhinitis, but remains controversial in asthma and atopic dermatitis. Some clinical symptoms, such as those related to food allergens, cannot be treated by desensitisation.
Autoimmunity is the failure of an organism to recognise its own constituent parts (down to the sub-molecular level) as “self”, which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Prominent examples are Systemic Lupus Erythematosus (SLE), Sjögren's syndrome and Rheumatoid Arthritis (RA). Autoimmune diseases are broadly classified into two categories, namely systemic diseases and organ-specific diseases. The precise aetiology of systemic autoimmune diseases is not identified. In contrast, organ-specific autoimmune diseases are related to a specific immune response including B and T cells, which targets the organ and thereby induces and maintains a chronic state of local inflammation. Examples of organ-specific autoimmune diseases include type 1 diabetes, myasthenia gravis, thyroiditis, multiple sclerosis, celiac disease, inflammatory bowel diseases, atherosclerosis, adrenalitis, polyendocrine syndromes, gastritis, pernicious anemia, ocular diseases such as uveitis, and inner ear diseases such as cochleitis.
Autoimmune reactions are thus directed to own cells or tissues, more particularly to “auto-antigens” i.e. antigens (of proteins) that are naturally present in the mammalian organism. In this mechanism, auto-antigens are recognised by B- and/or T-cells which activate the immune system to attack the tissue comprising the auto-antigen. It is well recognised that suppression of the immune system is beneficial and in some cases leads to partial or complete recovery of organ function in some instances. This kind of therapy is however not effective for all organ-specific autoimmune disease and up to date immune suppression can not be achieved in an antigen-specific manner. Current therapy makes use of non-specific immune suppression obtained by the use of corticosteroids and immunosuppressive agents, all exhibiting significant side effects related to the lack of specificity, thereby limiting their use and their overall efficacy.
Interestingly, for reasons that are far from being understood, the incidence of autoimmune diseases has doubled over the last 20 years, much in parallel to the increase observed in allergic diseases. Again, the cost related to the treatment of autoimmune diseases has increased enormously in recent years, adding a further argument to the need for a new form of therapy.
In the prior art, T-cell epitopes of allergens have been used for desensitisation purposes. Allergen-derived peptides containing one or a few T cell epitope(s) are used in animal experiments and in human beings in an attempt to inhibit specific T cell activation and induce a state of T cell unresponsiveness, such as described in the patent application WO93/08279. One human application of this concept is the administration of a peptide derived from the sequence of T cell epitopes present on the Fel d I allergen, by subcutaneous injections in cat-sensitive individuals (Wallner & Gefter (1994) Allergy 49, 302-308). An alternative, complementary approach of this concept has also been used in animal experiments. The peptides used were modified in such a manner as to keep the ability to bind to MHC-class II determinants on specific B cells, but these peptides lost their capacity to activate the corresponding T cells (O'Hehir et al. (1991) Int. Immunol. 3, 819-826).
The screening of the allergen Der p 2 of house mite with a set of overlapping peptides from this protein shows that one specific peptide p21-35 comprises a T-cell epitope which behaves as universal epitope and could be a suitable candidate for T cell anergy induction (Wu et al. (2003) J. Immunol. 169, 1430-2435, WO0170263). In a related publication it was shown that this peptide and derivatives thereof have an epitope specific effect on CD4+ CD25+ mediated apoptosis of antigen presenting B cells (Janssens et al. (2003) J. Immunol. 171, 4604-4612). The identification of this peptide however required an exhaustive screening of the allergen and there is no indication that for each and every antigenic protein, such a peptide with an apoptosis-inducing effect can be identified.
It is clear that there is a need for novel strategies or drugs for the prevention or treatment of immune diseases like allergic or autoimmune diseases, which are more effective, more specific, have less-side-effects, are curative instead of merely treating symptoms of disease and are easily accessible, more particularly at low cost. More particularly, for allergic diseases, there is a need for the development of new forms of therapy that are specific for the concerned allergens, that are safe and produce long-lasting beneficial effects.